The human genome is diploid, and a genome sequence is not complete unless all polymorphisms or variants are phased and assigned to specific chromosomes. Additionally, the entire chromosome landscape must be decoded, including complex structural variants in the genome (i.e., an-euploidy, translocations, inversions, duplications, loss of heterozygosity, etc). For example, balanced translocations occur in approximately 1 in 500 individuals, trisomy 21 occurs in as many as 1 in 650 live births, and extensive genome instability occurs in many cancers30-32. Accordingly, complete genome sequencing must be able to identify all complex genome variants.
There are a number of ultra-high-throughput sequencing technologies available (e.g., Illumina/Solex1, SOLiD2,3, Roche/4544, PacBio5-9, Ion Torrent10-12, etc.9) and under development [e.g., ZS Genetics9, IBM13 GE (U.S. Pat. No. 7,264,934), Oxford Nanopore14, Noblegen15, Bionanomatrix16, and GnuBIO9. While the cost of sequencing has decreased dramatically, the technology is still unable to completely sequence a human genome. There remain numerous regions of the human genome that are still not sequenced in the GRCh37 version of the genome, which consists of 249 scaffolds (http://www.ncbi.nlm.nih.gov/projects/genome/assembly/grc/data.shtml)17-19. Additionally, all current commercial technologies require a reference genome for a high quality assembly. While de novo genome assemblies are possible with short read technologies, the quality is low relative to resequencing projects.20 These problems limit the ability of next generation sequencing platforms to identify certain variants, such as large structural changes and repeated regions.
High throughput, long-read sequencing technologies are essential for resolving the complexities of the human genome. The human genome is diploid, meaning there are two copies each of 22 autosomes and two copies of the sex chromosomes (XX or XY). Long reads are essential to phase the genetic variants that are unique to each of the homologous chromosomes. Additionally, repetitive regions in the genome make sequencing impossible with short reads.
Recent advances in next generation sequencing technologies, along with the development of robust analytical methods, have given researchers the ability to determine the role of sequence variations in a variety of human diseases. However, the vast majority of these approaches produce results that are limited to finding polymorphisms while neglecting the importance of haplotypes. Today the most commonly studied variations are single-nucleotide polymorphisms (SNPs) and small insertions and deletions (InDels). This is because current generation sequencing methods, while proficient in identifying heterozygous loci, are unable to assign polymorphisms to one of the two homologous chromosomes, thus complicating the search for gene/disease associations. The HapMap and other projects are developing a haplotype map21-23, but new approaches are required to address the cis and trans relationships in variants that occur in rare genotypes (e.g., novel somatic mutations) or in altered genomes (e.g., cancer).
The lack of haplotype information obtained from current sequencing approaches limits scientists' ability to draw important biological and medical conclusions, namely, because lists of polymorphisms are classified as homozygous or heterozygous, they neglect the importance of the context of each polymorphism. As a consequence, researchers often focus only on the variants that occur in protein coding regions (the exome), since only their importance can be predicted. Without the context of knowing whether variants in intergenic regions are linked in cis and/or through long-range chromatin interactions to affected genes, it is not possible to predict whether such variants are detrimental. The principal advantage of haplotype resolved sequencing over standard whole genome sequencing (WGS) is that all polymorphisms are assigned to a specific chromosome (e.g., maternal vs. paternal), and links are established between mutations (or variants) in distant regulatory elements and cis-linked genes on the same chromosome.
The limitations associated with direct haplotype sequencing primarily revolve around the relatively short read-length and ‘phase insensitivity’ of the current platforms.24-26 There have been a few approaches to generate haplotype resolved sequence, but these are not consistent with the $1,000 genome goal, due to the complexity and additional cost associated with the processes upstream of sequencing.27-29 
Nanopore DNA sequencing technologies are attractive since they offer direct access to the DNA sequence information without amplification or complex post processing of the sequence information, and hold the promise of long reads at high speed 33, 34 There is a long history of research and development in various nanopore technologies. However, the promise has yet to be fully realized, and—in fact—no reads other than of specially constructed test DNA samples have been reported. Additionally, single base resolution has not been reported with nanopore technologies. The issues identified in previous research include:                1. Transduction speed of ˜1 base/□s (requiring high bandwidth electrical detection with concomitant noise and statistical fluctuation issues).        2. Longitudinal resolution greater than single base (typically ˜4 bases for biological pores) 35.        3. Massively parallel application is difficult with electrical readout mechanisms.        
Both biological and solid-state nanopore technologies have been investigated. For biological systems α-haemolysin36 and genetically-engineered MspA37 are the most common nanopores, and various techniques to slow the DNA translocation have been demonstrated, involving the use of enzymes38 or modification of the ssDNA strand to be interrogated with regions of dsDNA or other disturbances39 to slow the translocation. However, the difficulty associated with the large number of bases within the nanopore remains.35 
For solid-state pores the most common materials are silicon nitride and sapphire using ion- or electron-beam technologies to form the nanoscale pores. Graphene is another material that is attracting much attention40,41. Atomic layer deposition can be used post-lithography to refine the pore dimensions.42 Hybrid technologies, adding biological structures to solid-state pores have also been investigated.43 Notwithstanding all of this activity, the promise of nanopore technology has yet to be achieved.
One final issue with all of these approaches is the need to scale to massively parallel applications with cost-effective fabrication. Present fabrication approaches are dominated by direct-write technologies (electron-beam and ion-beam lithographies), which are not scalable to massively parallel architectures, nor compatible with widespread adoption of the technology at low cost. Electrical measurements are not easily scaled to parallel measurements in an ionic fluid environment, optical measurements provide the most promising route to parallelism—the issue is providing the necessary single base resolution.